Hydroxyalkyl alkyl derivatives of 5-nitroso-6-amino-1, 2, 3, 4-tetrahydro-2, 4-pyrimidinedione



l atented 8,

HYDROXYALKYL ALKYL DERIVATIVES OF NITROSO- 6 -AMINO- 1,2,3,4 -TETRAHY-BRO-2,4-PYRIMIDINEDIONE Viktor Papesch, Morton Grove, and Elmer F.Schroeder, Chicago, 111., assignors to G. D. Searle -& Co., Chicago,111., a corporation of Illinois No Drawing. Application June 24, 1950,Serial No. 170,256

6 Claims.

1 The present invention relates to new polysubstituted heterocycliccompounds and particularly to 5 nitroso-G-amino-1,2,3,4-tetrahydro-2,4-pyrimidinediones substituted on the nuclear nitrogen atoms by certainallcyl, cycloalkyl, hy-

droxyalkyl or aralkyl radicals.

The 5-nitroso-6-amino-1,2,3A-tetrahydro-2A- pyrimidinediones of thisinvention have the following structural iormula:

wherein the R radicals represent members of the group consisting ofalkyl, cycloalkyl, hydroxyalkyl and aralkyl groups and wherein at leastone of these R radicals has a molecular weight greater than 40.

Among the radicals which one of the substituents R may represent arenormal and branched propyl, butyl, amyl, hexyl, cyclobutyl, cyclopentyl,cyclohexyl, benzyl, phenethyl, phenylpropyl radicals as well ashydroxy-substitution products thereof such as hydroxy-ethyl,hydroxypropyl, dihydroxypropyl and the like. The other R radical is amember of the same type or methyl or ethyl. The two R radicals may bedifierent or identical.

We had found in the case of the 1,3-dialkyl-6- amino 1,2,3/i tetrahydro2,4 pyrimidinediones which are the subject of our previous applicationSerial No. 138,074 of January 11, 1950, that for a high degree oftherapeutic and especially diuretic activity, the presence of at leastone larger alkyl group was essential. Unless a group which has at leastthe size of a propyl group (molecular weight of 43,086) was present,these compounds were inactive. It has now been found, that exactly thesame structural requirement exists in the case of thenitroso-derivatives of these compounds. Thus the 1-isopropyl-3- ethyl 5nitroso 6 amino 1,2,3,4 mtrahydro-ZA-pyrimidinedione shows a strongdiuretic activity by the technique of Lipschitz (Journal of Pharmacologyand Experimental Therapeutics, 79:97, 1943) whereas the corresponding1,3-

diethyl compound in which the R groups have a weight of only 29.06, isquite inactive.

It is the object of this invention to provide novel chemical substancesof the type described above and methods for producing the same.

It is further the special purpose of this invention to providetherapeutically active compounds. Certain of our new compounds showvaluable therapeutic properties in improving cardiovascular and renalfunction. Such compounds also are valuable as active ingredient inparasiticidal compositions of matter.

The compounds whichcomprise this invention are useful as intermediatesin chemical synthesis, especially of 1,3-disubstituted xanthines andpteridinoids.

The new nitroso compounds are prepared by nitrosating the corresponding6-amino-1,2,3,4- tetrahydropyrimidinediones which are described in ourapplications Serial No. 138,074,,filed J anuary 11, 1950, now U. S.Patent No. 2,567,651, dated September 11, 1951, and Serial No. 172,379filed July 6, 1950, now Patent No. 2,596,041. The nitrosation is carriedout by dissolving the 6- amino 1,2,3,4 tetrahydro 2,4 pyrimidinedionesin water or dilute alcohol, or by preparing a fine suspension, thenadding at least one molecular equivalent of an alkali nitrite, heatingto a temperature somewhat below the boiling point and acidifying. Theexothermic reaction proceeds rapidly. The yield is, in most instances,almost quantitative. The nitroso compounds are usually recrystallizedfrom water. Their color varies, as indicated hereinafter in theexamples, from a light pink to a dark purple. Most of these compoundstend. to decompose 1n the melting point tube. For purposes ofidentification, they were converted to the corresponding xanthine. Thenitroso compound Was reduced withan agent such as ammonium sulfide tothe 5,6-diamino-1,2,3,4=tetrahydro-2,4-pyrimidinedione. The latter washeated with'formie acid to prepare the 5-formylamino compound which wascyclized by heating for a short time with alkali to form the xanthine.

The following examples illustrate in detail certain of the compoundswhich comprise this invention, and methods for producing them. Theinvention is not to be construed as limited in spirit or in scopethereby. It will be apparent to EXAMPLE 11,3dim-propyl-5-nitros0-6-amino-1,2,3,4-

tetrahydro-2,4-pyrimidinedione This nitroso compound is reduced with 20g. of ammonium sulfide in a 10% aqueous solution. The mixture is heatedon the steambath until the odor is no longer noticeable and the sulfuris filtered off. The 1,3-di-n-propyl-5,6-diamino-1,2,3,4-tetrahydro-2,4-pyrimidinedione is' purified by repeatedrecrystallization from dilute alcohol. The white crystals melt at about129-131 C. The diamino compound is boiled with a sufficient amount of anaqueous solution'of formic acid to'bring the pH to 2 until the1,3-di-n-propyl-5- formylamino 6 amino 1,2,3,4-tetrahydro-2,4pyrimidinedione begins to precipitate. Recrystallization from 10%ethanol yields a white powder which melts at 203-204 C. 150 ml. of waterand sumcient 70% sodium hydroxide are added to raise the pH to 10. Thesolution is heated to boiling for minutes, stirred with charcoal andfiltered. Aceticacid is added to the filtrate to lower the pH to about 5and, after cooling, the l-aedi-n-propyl xanthine is collected on afilter. Several recrystallizations from 50% ethanol yield white crystalsmelting at about 204-206 C.

EXAMPLE 2 1-n-propyZ-3-ethyZ-S-nitroso-6-amino-12,3,4-

tetmhydro-2,4-pyrimidinedione A solution of 60 g. of a mixture of 90% ofthe 1-n-propyl-3-ethyl-6-amino-1,2,3,4 tetrahydro 2,4-pyrimidinedioneand 10% of l-ethyl-3-npropyl-6-amino 1,2,3,4-tetrahydro 2,4pyrimidinedione in 600 ml. water is treated with 21 g. of, sodiumnitrite at 75 C. 21 g..of acetic acid are added in the course of severalminutes, the temperature rising to about 85 C. After 5 minutes standing,the mixture is cooled and filtered. The reddish-purple crystals,recrystallized from 1500 m1. of boiling water, melt at about lad-187 0.They consist primarily of 1-V-npropyl-3-ethyl-5-nitroso-6-amino-123,4tetra- 4 hydro-2,4pyrimidinedione with only a minor admixture of the1-ethyl-3-n-propyl-isomer. This product is reduced to the 5,6-diaminocompound, the latter is formylated to the l-n-propyl-3-ethyl-5-formylamino 6 amino 1,2,3,4-tetra hydro-2,4-pyrimidinedione,according to the method of Example 1. Cyclization with sodium hydroxideyields the l-ethyl-3-n-propyl xanthine, which melts at about 175-6 C.upon recrystallization from 20% ethanol. If the pure 3-ethyl-1- propylisomer is used, the recrystallized nitroso compound melts at about201-203 C.

EXAMPLE 3 1-isopropyl-3-ethyl-5-nitroso-6-amino-1,2,3,4-

tetrahydro2,4-pyrimidinedi0ne A solution of 90 g. ofl-isopropyl-3-ethyl-6- amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in1100 ml. of water is treated with 32 g. of sodium nitrite at 95 C.Addition of 32 m1. of glacial acetic acid produces no pronounced rise intemperature, an observation characteristic for the deactivating effectof a branched alkyl group in a-pOSltlOD. to the acidic nitrogen in thepyrimidine. After 10 minutes of standing the lisopropyl 3ethyl-5-nitroso-6-amino-1,23,4- tetrahydro-2,4-pyrimidinedione iscollected on a filter and washed with water. The glittering dark purplecrystals melt and decompose near 200 C. with gas development. Reductionby the method of Example 1 yields the 1 isopropyl-3- ethyl-5,-diamino-1,2,3,4-tetrahydropyrimidinedione which, afterrecrystallization from water, melts at about 62 to 64 C.

EXAMPLE 41,3-di-n-butyl-5-nitroso-6-amino-1,2,3,4-tctrahydro-2,4-pyrimidinedione200 g. of 1,3-di -n-buty1-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedionein 2300 ml. of water and 1400 ml. ethanol are treated with 64 g. ofsodium nitrite at to 82 C. 64 ml. glacial acetic acid are added asrapidly as the exothermic reaction permits. After 5 minutes of standingthe mixture is cooled, filtered and washed with water. The1,3-di-n-butyl-5-nitroso-6-amino- 1,2,3,4 tetrahydro 2,4 pyrimidinedioneforms purple crystals. By the method of Example 1 this compound isconverted first to the 1,3-di-nbutyl-5,6-diamino-l,2,3,4-tetrahydro-2,4-pyrimidinedione, then to the1,3-di-n-butyl-5-formylamino 6amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and finally to1,3-di-n-butyl-xanthine which melts at about 189 to 191 C. after re,-crystallization from 55% ethanol.

EXAMPLE 5 1-11.-butyl-3-methyl-5-nitroso-6-amino-1,2,3,4-

' tetrahydro-2,4-pyrimidinedione A solution of 50 g. ofl-n-butyl-3-methyl-6- amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in660 ml. of water is treated at C., first with 16.4 g. of sodium nitriteand then with 17.7 ml. of glacial acetic acid, the temperature rising toC. The purple-red compound first precipitates in amorphous aggregates.On cooling, crystals form, probably due to hydration. Thisl-n-butyl-B-methyl 5 nitroso-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione is converted by the method of example 1,first to the 1-n-butyl-3- methyl-5,6-diamino 1,2,3,4tetrahydro-2,4-pyrimidinedione, then to the 1-n-butyl-3-methyl-5-formylamino 6 amino-123,4 tetrahydro-2,4 pyrimidinedione and finally to1-methyl-3-butyl Xanthine, which upon recrystallization from 40% ethanolforms white crystals melting at 208 to 209.5 C.

EXAMPLE 6 1 n butyZ-3-ethyl-5-nitro3o-fi-amino 1,23,4-

tetrahydro zA-pyrimidined'ione 17.2 g. of1-n-butyl-3-ethyl-6-amino-1,23,4- tetrahydro-2,4pyrimidinedionemonohydrate is dissolved in 125 ml. of 20% aqueous ethanol by heating to80 C. While the temperature is maintained at about 80 to 85 0., thereare added first 5.45 g. of sodium nitrite and then 20 ml. of 30% aqueousacetic acid, dropwise, in the course of 10 minutes. A heavy purpleprecipitate is formed. After cooling these crystals are filtered, washedwith water and dried at 80 C. They melt with decomposition at about 175to 177 C. This nitroso compound is converted by, the usual method to the1 n butyl-3-ethyl-5,6-diamino- 1,2,3,4tetrahydro-2,4 pyrimidinedione,then to the l-n-butyl-3-ethyl-5-formy1amino-6 amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione and finally to the1-ethyl-3-n-butyl-xanthine. Recrystallization from 10 parts of 30%aqueous ethanol yields white needles which melt at about 168 to 169 C.

EXAMPLE 7 1 -,isobut yl-3-methyZ-5-nitroso-6-amino 1,23,4-tetrahydro-2,4-pyrimidinedine A solution of 18 g. ofl-isobutyl-S-methyl-G- amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in240 ml. of water is treated at 90 C. first with 5.9 g. of sodium nitriteand then with 6.4 ml. glacial acetic acid. The temperature rises to 100C. with some gas development. Afterfi minutes of standing, the mixtureis cooled, filtered and washed with water. The purple l-iso-butyl- 3methyl nitroso-B-amino 1,2,3A-tetrahydro-2,4-pyrimidinedione isconverted to the 1-iso-buty1-3methyl-5,6-diamino 1,2,3,4-tetrahydro-2,4-pyrimidinedione, then to the 1 isobutyl 3 methyl 5 formylamino 6 amino-1,2,3,4-tetrahydro 2,4 pyrimidinedione and finally to1-methyl-3-isobutyl xanthine which, recrystallized from 50% ethanol,melts at about 199 to 201 C.

EXAMPLE 8 1 allyl s ethyl-5nitros0 6-'amino12,3,4-

' tetrahydro2,4-pyrimidinedione I A solution of 150 g. of1-allyl-3-ethyl-6-aminol,2,3,4-tetrahydro-2,4-pyrimidinedione in 340 ml.Water is treated at 75 C. with 56 g. of sodium nitrite and then slowlywith 60 ml. of acetic acid, keeping the reaction temperature at about 80C. After standing and cooling, water is added to the crystallinesuspension. The heated crystals are collected on a filter, washed andrecrystallize'd from water. The 1-allyl-3-ethyl-5-nitroso-G-amino-1,2,3,4-tetrahydro-2,4 pyrimidinedione forms purple crystalswith a metallic sheen, which melt at about 156-158 C. This nitrosocompound has the structural formula:

CHFCH-CH:

/N HzN C o=o ON-C 1LT-C2H5 heating to 75 C.

Treatment as in Example 1 yields the 1-allyl -3- ethyl 5,6diamino-1,2,3,4tetrahydro-2,4- py rimidinedione, which is formylated tothe 1 al1yl-3-ethyl-5-formylamino 6 amino 1,2,23,4-tetrahydro-2,4-pyrimidinedione. The latter is cyclized to the1-ethyl-3-al1yl xanthine which, upon recrystallization from water, meltsat about 185 to 187 C. I

EXAMPLE 9 i-cyclohexyZ-B-ethyl 4 5 nitroso 6 amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione Crude 1-eyclohexyl-3-ethyl 6amino-1,23,4- tetrahydro-2,4-pyrimidinedione containing approximately 30g. of the pure pyrimidine is dissolved in 1500 ml. of 30% aqueousethanol by 17.3 g. of sodium nitrite are added and, while stirring at 75to C., 60 m1. of 30% aqueous acetic acid are slowly added. After coolingthe purplish precipitate is collected on a filter and washed with water.For purification the precipitate is twice stirred for several minutes atroom temperature with 250 ml. of ethanol, filtered and washed with 95%ethanol. The impurities are thus dissolved, leaving the 1 cyclohexyl 3ethyl-5-nitroso-6- amino-1,2,3,4'-tetrahydro-ZA-pyrimidinedionc aspurple. crystals which melt with decomposition at about 215 to 216 C.They are converted by the method of Example 1 to the 1-cyclohexyl-3-ethyl 5,6 diamino 1,2,3,4 tetrahydro 2,4- pyrimidinedione, then to the 1-cyclohexyl-3- ethyl- 5-formylamino 6 amino1,2,3,4-tetrahydro-2,4-pyrimidinedione and finally to the 1-ethyl-3-cyclohexyl xanthine, which forms needles melting at about206-208 C.

EXAMPLE l0 1,3-d2'beneyl 5 m'trOso 6 amino 1,23,4-

tetrahydro-2,4-pyrimidinedione :181 g. of 1,3-dibenzyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in 1400 m1. of 60% ethanol aretreated with 50 g. of sodium nitrite. The stirred solution is heatedslowly toboiling and treated with 50 ml. of acetic acid, as rapidly asthe exothermic reaction permits. After 5 minutes of standing, themixture is cooled and the 1,3-dibenzyl 5 nitroso 6 amino 1,23,4-tetrahydro-2,4-pyrimidinedione collected on the filter. The light pinkcrystals, after recrystallization from 60% ethanol, melt at about 222 to224 C. This compound is converted by the method of example 1, first tothe 1,3-dibenzyl- 5,6-diamino-1,2,3A-tetrahydro-2A pyrimidinedone, thento the 1,3-dibenzyl 5 formylamino- 6-amino-1,2,3,4-tetrahydro2,4-pyrimidinedione and finally to the 1,3-dibenzyl xanthine, whichmelts at about 214 to 215 C.

EXAMPLE 11 I-methyZ-B-(B-hydromyethyl) 5 nitroso 6eamino-1,2,3,4-tetrahydro-ZA-pyrimidinedwne A solution of 51 g. of1-methyl-3-(fl-hydroxy ethyl) -6-amino-1,2,3,4 tetrahydro2,4-pyrimidinedione in 500 ml. of boiling water is nitrosated bytreatment with 19 g. of sodium nitrite and 18.2 ml. of glacial aceticacid. The resulting reaction mixture is cooled and the 1-methyl-3-(B-hydroxyethyl)-5-nitroso 6 amino-1,2,3,4-. tetrahydro2,4-pyrimidined1one collected-on a awards" filter, washed with water anddried. This compound has the structural formula: I l 1 I V CH3 '7Amixture of 100 ml. of 28% ammonia water and 200 g. of ice is treatedwith hydrogen sulfide until 25 g. are taken up. To this solution areadded 50 g. of the above nitroso compound. After the addition, themixture is boiled for two hours, then filtered and evaporated. Theresidue of 1 methyl 3 -(;8-hydroxyethyl) 5,6 diaminol3,3,4-tetrahydroZA-pyrimidinedione obtained by this procedure, is heated with 170 ml. offormic acid until it dissolves. The hot mixture is treat.- ed withcharcoal and filtered. The filtrate is refluxed for 2 /2. hours and thesolution is.evapo-. rated in vacuum. The hot solution is diluted with.150 ml. of. hot water, treated with charcoal and filtered- 30 g. of.calcium oxide are added to make the mixture strongly. alkaline and theresulting. solution is boiled 3% hours. During this boiling. periodsuificient calcium oxide (about 10 g.) is added to maintain alkalinity;The cooled solution is brought to pH 4 withhydrochloric-acid, cooledwith ice, and allowed: to crystallize. The crystals ofl-p-hydroxyethyl-3- methyl xanthine are removed by filtration andrecrystallized-from water, using. activated charcoal. This compoundmelts at about 23.5. to 245?.

EXAMPLE 12 1 -(B-hydroxyeth1/Z) -3-methyZ-5-nitroso-6-amino-1,2,3,4-tctrahydro-2,4-pyrimidinedione 120 g. of 1-([i-hydroxyethyl)- 3 methyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in 500 ml. of water arenitrosated by adding 45 g. of sodium nitrite, boiling and then adding 30ml. of glacial acetic acid. The charge is heated for a few minutes. Onchilling, a precipitate of the 1- (/B-hydroxyethyl)-3-methyl-5-nitroso-6 amino- 1,2,3,4 tetrahydro 2,4 pyrimidinedioneforms which is collected on a filter. This compound has the followingstructural formula:

CHECHQOH Into224 ml. of 28% ammonium hydroxide and 450 ml. of ice ispassed hydrogen sulfide until-the uptake is 55 g. The solution is thenheated to boiling and 112 g. of the above compound are added in smallportions. This. mixture is boiled for 2 /2 hours, then filtered with theaid of decolorizing charcoal. The filtrate is evaporated on the steambath'until nearly dry; There is obtained in this .way 1-(,B-hydroxyethyl) -3-methyl- 5,6 -diami'no-l,2',3,4 tetrahydrQ-ZApyrimidined ne I 985g. Ofthe above compound are refluxed with 400ml. offormic acid for 3 hours. Thejformic. acid is then removed byvacuumdistillation. and theresidl B'is taken up in, about 1 liter of water. Tem x ure is filte d o rem v sulf an BQ e,- 0! calciumoxide are added "tothe filtrate; "The suspension is-boiled for 2 hours. The resultingsolution is made slightly acid with concentrated hydrochloric acid and aprecipitate forms. The charge is chilled and filtered. The 1-methyl-3-B-hydroxyethyl xanthine is washed with water and dilute alcohol, andthen recrystallized from water with the aid of decolorizing charcoal.The product thus. obtained melts at about 276 to 277 0.

EXAMPLE 13 1 (e-hydroryethyl) -3-ethyZ5-nitroso-6:amino1,2,3,4etetrahydro-2,4-pyrimidinedione To a solution of 30 g. of l-(3-hydroxyethyll-3- ethyl-B-amino-12,3,4-tetrahydro-2,4-pyrimidinedionein 150 ml. of water, heated to C., are added 10.9 g. of sodium nitrite.With stirring 40 ml. of an approximately 30% aqueous solution of aceticacid are added dropwise in a period of 10 minutes, the temperature beingmaintained at about 90 to C. On cooling, purplish crystals of 18-hydroxyethyl) 3 ethyl 5 nitroso-6- amino-1,2,3,4-tetrahydro 2,4pyrimidinedione separate. These are filtered 01f, washed with water anddried at 80 C. to melt with decomposition at about 1'72173 C. Thiscompound is converted by the method of Example 12 to the l.-(fl-hydroxyethyli-ii ethyl 5,6-diamino -l,2,3,4- tetrahydro-ZApyrimidinedione, then to 1 (flhydroxyethyl)3-ethyl-5-formylamino-6-amino- 1,2,3,4-tetrahydro-2,4-pyrimidinedioneand finally to the 1-ethyl-3-(fi-hydroxyethyl) xanthine. The sodium saltof this xanthine derivative is insoluble in water. Recrystallization ofthe base from water produces white crystals which melt at about 211 to212 C.

We claim:

1. The hydroxyalkyl-alkyl-5-nitroso-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinediones of the structural formula:

wherein one of R radicals is a lower hydroxyalkyl and the other a loweralkyl group.

2. The lehydroxyalkyl- 3-alkyl- S-nitroso- 6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinediones of the structural formula:

lli'ydroxyalkyl N ON-C N-Alkyl wherein the alkyl radical is a loweralkyl radical and the'hydroxyalkyl radical is a lower hydroxyalkylradical.

3. The hydroxyalkyl-alkyl-5-nitroso-6+amino-1,2,3,4-tetrahydro-ZA-pyrimidinediones of the structural formula:

R t H m-o o=o 9 wherein one of the R radicals is a p-hydroxyethylradical and the other is a lower alkyl radical.

4. A compound as in claim 3 wherein one R is a fi-hydroxyethyl radicaland the other is a methyl radical.

5. l-(p-hydroxyethyl)-3-methy1-5-nltroso-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidined1one.

6. 1 (p-hydroxyethyl) -3-ethyl-5-nitroso- 6amino-1,2,3A-tetrahydro-2,4-pyrimidinedione.

VIKTOR PAPESCH. ELMER F. SCHROEDER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Beilstein, Vlerte Auflage, vol. 24. p. 515.

1. THE HYDROXYALKYL-ALKYL-5-NITROSO-6-AMINO1,2,3,4-TETRAHYDRO - 2,4 -PYRIMIDINEDIONES OF THE STRUCTURAL FORMULA: